Tezosentan increases nitric oxide signaling via enhanced hydrogen peroxide generation in lambs with surgically induced acute increases in pulmonary blood flow

Sanjiv Kumar, Peter E. Oishi, Ruslan Rafikov, Saurabh Aggarwal, Yali Hou, Sanjeev A. Datar, Shruti Sharma, Anthony Azakie, Jeffrey R. Fineman, Stephen M. Black

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

We have previously shown that acute increases in pulmonary blood flow (PBF) are limited by a compensatory increase in pulmonary vascular resistance (PVR) via an endothelin-1 (ET-1) dependent decrease in nitric oxide synthase (NOS) activity. The mechanisms underlying the reduction in NO signaling are unresolved. Thus, the purpose of this study was to elucidate mechanisms of this ET-1-NO interaction. Pulmonary arterial endothelial cells were acutely exposed to shear stress in the presence or absence of tezosentan, a combined ET A/ETB receptor antagonist. Shear increased NOx, eNOS phospho-Ser1177, and H2O2 and decreased catalase activity; tezosentan enhanced, while ET-1 attenuated all of these changes. In addition, ET-1 increased eNOS phospho-Thr495 levels. In lambs, 4h of increased PBF decreased H2O2, eNOS phospho-Ser1177, and NO X levels, and increased eNOS phospho-Thr495, phospho-catalase, and catalase activity. These changes were reversed by tezosentan. PEG-catalase reversed the positive effects of tezosentan on NO signaling. In all groups, opening the shunt resulted in a rapid increase in PBF by 30 min. In vehicle- and tezosentan/PEG-catalase lambs, PBF did not change further over the 4 h study period. PVR fell by 30 min in vehicle- and tezosentan-treated lambs, and by 60 min in tezosentan/PEG-catalase-treated lambs. In vehicle- and tezosentan/PEG-catalase lambs, PVR did not change further over the 4 h study period. In tezosentan-treated lambs, PBF continued to increase and LPVR to decrease over the 4 h study period. We conclude that acute increases in PBF are limited by an ET-1 dependent decrease in NO production via alterations in catalase activity, H2O2 levels, and eNOS phosphorylation.

Original languageEnglish (US)
Pages (from-to)435-447
Number of pages13
JournalJournal of cellular biochemistry
Volume114
Issue number2
DOIs
StatePublished - Feb 1 2013

Keywords

  • Biomechanical forces
  • Catalase
  • ENOS
  • Endothelin-1
  • Hydrogen peroxide
  • Nitric oxide
  • Pulmonary blood flow

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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